Background: Natural enzymes mouthwash is marketed as salivary substitutes to treat xerostomia or dry mouth. However, there are minimal published studies that investigate its efficacy. Therefore, the purpose of this study is to evaluate the efficacy of natural enzymes moisturising mouthwash to treat xerostomia. Methods: A double-blind, parallel group randomised control clinical trial involving N = 49 adult participants with xerostomia was carried out. Intervention group received natural enzymes moisturising mouthwash (with the active ingredients lactoferrin, lysozyme, lactoperoxidase and glucose oxidase); while control group received benzydamine mouthwash. Mouthwashes were repacked, labelled with specific code, and were given to participants by third-party. Subjects were instructed to rinse with the mouthwash 4 times per day at a specific period, for 2 weeks. Symptoms of xerostomia were assessed using Xerostomia Inventory at day 0 and 14 of the 2-week period; together with the assessment of Clinical Oral Dryness Score (CODS), and measurement of resting and stimulated salivary flow rate. Data collected were analysed using SPSS Version 23.0. Data were compared within each arm before and after using the mouthwashes; and between both arms after using the mouthwashes. Results: A total of 48 participants completed the clinical follow-up, and n = 1 had lost of follow-up. From the 48 participants, n = 23 received natural enzymes mouthwash, while n = 25 received benzydamine mouthwash. Intervention group achieved greater reduction in symptoms of xerostomia from the baseline than control group. Intervention group also showed significantly better improvements in the cognitive perception of dry mouth and oromotor function such as chewing, swallowing and speech of the participants as well as reduction in waking up at night to drink water (p<0.05). The CODS and resting salivary flow rate were also significantly improved in intervention group (p<0.05). Natural enzymes mouthwash was also rated more pleasant to use than benzydamine mouthwash. Conclusion: Use of natural enzymes mouthwash improved signs and symptoms of xerostomia and is potentially effective to treat xerostomia. Clinical Trial Registration Number: This study was retrospectively registered in ClinicalTrials.gov ID NCT05640362 on 7 December 2022.